Clavulanic acid and its derivatives. Structure elucidation of clavulanic acid and the preparation of dihydroclavulanic acid, isoclavulanic acid, esters and related oxidation products

Abstract

Clavulanic acid, a novel β-lactamase inhibitor from Streptomyces clavuligerus, has been shown to be Z-(2R,5R)-3-(β-hydroxyethylidene)-7-oxo-4-oxa-1 -azabicyclo[3.2.0]heptane-2-carboxylic acid (1). The structure and absolute stereochemistry was confirmed by X-ray analysis of the p-nitrobenzyl and p-bromobenzyl esters, (14) and (15). The conversion of clavulanic acid into a variety of esters and acyl derivatives is described. An account of its isomerisation to the E isomer (30) and the formation of an oxetane (45) as a by-product of the photolysis of the phenacyl ester (18) is given. The reduction and oxidation of acid (1) under a variety of conditions has also been examined in detail.